[Study of FGFR2 status in gastric cancer by immunohistochemistry and fluorescent in situ hybridization]. / Izuchenie statusa FGFR2 pri rake zheludka metodami immunogistokhimii i flyuorestsentnoi gibridizatsii in situ.

BACKGROUND: Assessment of FGFR2 status in gastric cancer is an important task, without clarification of which it is impossible to identify a cohort of patients in whom the best response to treatment with anti-FGFR2 drugs could be obtained. OBJECTIVE: To conduct a comparative analysis of the expression and amplification of the FGFR2 gene in gastric cancer in primary tumors and metastases in the lymph nodes. MATERIAL AND METHODS: FGFR2 status was studied in 61 patients with stage III gastric adenocarcinoma using an immunohistochemical method (Abcam clone EPR24075-418, R&D clone 98706, Santa Cruz clone C-8, Abcam clone 1G3) and FISH. RESULTS: The antibody Abcam clone EPR24075-418 was found satisfactory for the immunohistochemical study of FGFR2. FGFR2 expression was detected in 26 (43%) cases, amplification in 5 (8%) cases. Amplification of FGFR2 in 4 cases out of 5 was accompanied by the expression of 3+, in 1 case - 2+. Discordance between FGFR2 expression in primary tumor and lymph node metastases was revealed in 13 (21%) cases. CONCLUSION: Clone EPR24075-418 showed the best result in assessing the expression of FGFR2: the correlation with FISH results in reaction 3+ was 100%. Due to the high heterogeneity of FGFR2 expression, it is recommended to either examine the material of the primary tumor and metastasis, or evaluate a large volume of the primary tumor.

[Microsatellite instability and DNA mismatch repair deficiency detection in tumors of various sites]. / Opredelenie mikrosatellitnoi nestabil'nosti i sostoyaniya genov reparatsii nesparennykh nukleotidov DNK pri opukholyakh razlichnykh lokalizatsii.

Microsatellite instability, which is caused by a deficiency in the DNA unpaired nucleotide repair system, is an important pathogenetic event for some tumors. In addition, the detection of this molecular feature becomes an independent prognostic factor in the course of the disease and a predictor for the appointment of therapy with immune checkpoint inhibitors. Immunohistochemistry is a reliable and available method for detecting a deficiency in the DNA mismatch repair system, and it has recommended as a screening for hereditary syndromes associated with microsatellite instability. This article discusses the advantages and disadvantages of this research method from the point of view of the practitioner.

Laboratory biomarkers of an effective antitumor immune response. Clinical significance.

The modern checkpoint inhibitors block the programmed death-1 receptor and its ligand, cytotoxic T-lymphocyte-associated antigen 4 on tumor cells and lymphocytes, that induces cytotoxic reactions. Nowadays, there are no approved clinical and laboratory predictor markers of immune therapy efficacy, which would allow a more personalized approach to patient selection and treatment. The aim of this review is to analyze possible biomarkers of efficacy for treatment with checkpoint inhibitors according to the pathogenic mechanisms of drug action. The review revealed possible predictive biomarkers, that could be classified to 3 groups: biomarkers of high mutagenic potential of the tumor, biomarkers of high activity of adaptive immunity, biomarkers of low activity of the tumor microenvironment. The determination of the described markers before the start of therapy can be used to formulate a treatment regimen, in which the use of various immunomodulatory drugs, inhibitors of proinflammatory cytokines, angiogenic molecules, and probiotics can be considered.

Self-assembled polypeptide nanoparticles for intracellular irinotecan delivery.

In this research poly(l-lysine)-b-poly(l-leucine) (PLys-b-PLeu) polymersomes were developed. It was shown that the size of nanoparticles depended on pH of self-assembly process and varied from 180 to 650nm. The biodegradation of PLys-b-PLeu nanoparticles was evaluated using in vitro polypeptide hydrolysis in two model enzymatic systems, as well as in human blood plasma. The experiments on the visualization of cellular uptake of rhodamine 6g-loaded and fluorescein-labeled nanoparticles were carried out and the possibility of their penetration into the cells was approved. The cytotoxicity of polymersomes obtained was tested using three cell lines, namely, HEK, NIH-3T3 and A549. It was shown that tested nanoparticles did not demonstrate any cytotoxicity in the concentrations up to 2mg/mL. The encapsulation of specific to colorectal cancer anti-tumor drug irinotecan into developed nanocontainers was performed by means of pH gradient method. The dispersion of drug-loaded polymersomes in PBS was stable at 4°C for a long time (at least 1month) without considerable drug leakage. The kinetics of drug release was thoroughly studied using two model enzymatic systems, human blood serum and PBS solution. The approximation of irinotecan release profiles with different mathematical drug release models was carried out and allowed identification of the release mechanism, as well as the morphological peculiarities of developed particles. The dependence of encapsulation efficiency, as well as maximal loading capacity, on initial drug concentration was studied. The maximal drug loading was found as 320±55µg/mg of polymersomes. In vitro anti-tumoral activity of irinotecan-loaded polymersomes on a colon cancer cell line (Caco-2) was measured and compared to that for free drug.

[SUPPRESSION OF TUMOR GROWTH AFTER XENOGRAFTING OF HUMAN COLORECTAL CARCINOMA CELLS].

Previously we've described the obtainment of a subpopulation of cancer stem cells from a human colorec- tal carcinoma cell line MIP101. These cells possess elevated clonogenic and tumorigenic capacities. According to our data, depletion of stem compartment in a cancer cell population blocks its tumorigenicity. The current work is dedicated to the comparison of tumorigenic potential between cell populations with enriched or depleted stem compartment. We show that tumor growth following xenografting of enriched stem cell population can be suppressed by intramuscular injections of ganciclovir. Thus, we report a method to obtain a cell population with high Oct4 promoter expression within the MIP101 colorectal carcinoma cell line and to eliminate these cells from the population in vitro as well as in vivo.

[RESULTS OF DIAGNOSTICS AND TREATMENT OF ADRENOCORTICAL CANCER].

The results of examination and treatment of 96 patients with adrenocortical cancer (ACC) were analyzed. Local forms of ACC (I and II stages (T1-2N0M0) were found in 19 patients, locally advanced forms (III stage (T1-4NIM0; T3-4N0M0) - in 62 cases and metastatic forms of ACC (IV stage (TxNxM1) - in 15 patients. The diagnostic approach to ACC was optimized. It allowed identifying ACC on early stages of oncological process and staging of oncological process preoperatively in order to justify a rational treatment option. Surgical interventions were performed on 85 patients. The authors used an open access in 75 patients and endovideosurgical - in 10. The most common way of surgery was to remove an affected adrenal gland with fat of upper paranephrium and regional for adrenal lymph nodes (n=56). The adrenalectomy and nephrectomy were fulfilled on 23 patients. A removal of the right adrenal with tumor and thrombus of the interior vena cava was carried out in 2 patients. Some patients (n=4) underwent the explorative interventions. Combined treatment was applied in 28 patients with ACC of III stage. This gave a possibility to increase their life-span from 17,5±8,4 to 36,3±6 months. The overall 3-year survival rate for patients with ACC was 41,2% and 5-year survival observed in 18,7%. An application of modified treatment-and-diagnostics algorithm allowed increasing detection of patients with local and locally advanced forms of ACC in 2,5 times. Therefore, the application of rational treatment options have reduced the number of intraoperative complications from 38,8% to 10,2% and postoperative complication rates- from 61,1% to 20,4%, the lethality :rate - from 7,1% to 0% in early postoperative period. These measures have increased the life-span and life quality in 2 times.

[Chemotherapy for malignant tumors: problems and prospects].

This article is about the possibilities of increasing effectiveness and reducing toxicity in standard chemotherapy for cancer. Three possibilities are described: mechanisms of and overcoming multidrug resistance, selective transportation and drug delivery using vectors and artificial vehicles, and individualization of anticancer therapy.

[Prognostic values of the clinical, morphological and molecular biological characteristics of colon adenocarcinoma].

OBJECTIVE: to estimate the predictive and prognostic factors using morphological studies in patients with colon cancer to increase survival rates. SUBJECTS AND METHODS: Immunohistochemical examination was made in 582 patients with colon adenocarcinoma, by determining 11 different indicators relating to the development of the tumor and its treatment. RESULTS: The simultaneous determination of the chemokine receptor CXCR4 and proliferative activity (Ki-67 expression) can define disease prognosis in view of relapse-survival rates in patients with Stage II colon cancer after radical surgical treatment. CONCLUSION: Thymidylate synthase and thymidine phosphorylase are of predictive value. The immunohistochemical examination of other markers, such as ALDH1, CCR10, ERCC-1, DYPD, topoisomerase II alpha, and class III beta-tubulin for the choice of treatment policy for patients with colon cancer has indicated that they are of no value.

[Immunohistochemical examination of MSH2, PMS2, MLH1, MSH6 compared with the analysis of microsatellite instability in colon adenocarcinoma].

Adenocarcinoma of the colon in 10-20% is associated with microsatellite instability, which can occur both in sporadic cancers and in hereditary nonpolyposis colon cancer. Our analysis of 195 cases of adenocarcinoma of the colon showed that microsatellite instability (MSI-H) was found only in 1.5% of patients. Subsequent choice of patients with suspected hereditary Lynch syndrome led to the identification of additional 17 patients with microsatellite instability. They passed an analysis of genes of repair system of unpaired nucleotides of DNA. The study showed that immunohistochemical staining of MSH2, MSH6, MLH1, PMS2 could effectively conduct a preliminary screening of the Lynch syndrome but was unable to divide cases of sporadic and hereditary MSI-H colon cancer.

[Proliferation of cancer stem cells in colorectal adenocarcinoma].

Correlation between level of ALDH1 expression and metastases development in patients with colorectal adenocarcinoma was not revealed. Proliferation of stem cancer cells (ALDH1-positive) was significantly lower comparatively ALDH-1 negative tumor cells (p < 0.001). Proliferation of stem cancer cells vary from 0,1% to 10%.

[Morphological assessment of predictive factors in adenocarcinoma of the colon].

Immunohistochemical investigation of 15 different markers in colon adenocarcinoma was carried out. Prognostic significance showed chemokine receptor CXCR4 and Ki-67. Predictive significance was revealed for thymidylate synthase (TS) and thymidine phosphorylase (TP).

[Results of chemotherapy for gynecologic cancer patients in ambulatory care].

Russian Academy for Further Medical Education, St. Petersburg A clinical-statistical analysis of chemotherapeutic treatment of 198 gynecological cancer patients in an outpatient clinic and 226 ones in a hospital. It was concluded that was no difference in the treatment effectiveness, as well as in the incidence of hematological and non-hematological complications.

[Possibilities of palliative operations in patients with intrapulmonary metastases of renal cancer].

Results of treatment of 51 patients with intrapulmonary metastases of renal cancer were analyzed. Surgical interventions in volume of complete cytoreduction were made in 31 of them. All the patients were followed-up after operations at the period from 3 through 68 months. A multi-factor analysis has shown that surgical metastasectomy gives reliably better results of treatment of patients with disseminated renal cancer. Regressive analysis in the group of operated patients has shown that involvement of the lymph nodes of the bronchopulmonary group and mediastinum gave reliably worse results of treatment of this group of patients.

[Cytoreductive operations in complex treatment of patients with intrapulmonary metastases of colorectal carcinoma].

An analysis of results of treatment of 112 patients with metastases of intrapulmonary colorectal carcinoma (CRC) for the period from 1990 to 2006 has shown that cytoreductive opera tions for excision of the metastases are an effective method of treatment of this category of patients which allows a two times increased survival median as compared with analogous index in the group of patients exposed to palliative chemotherapy. Palliative chemotherapy fails to have statistically significant influence to survival of patients who have ablated intrapulmonary CRC metastases in the volume of complete cytoreduction.

[Use of liquid-based endometrial cytology in breast cancer patients receiving tamoxifen].

Fifty-four (54) breast cancer patients, receiving tamoxifen, were enrolled into an evaluation of the status of the endometrium. Liquid-based cytology and immuno-cytochemical analysis were used for assessment. Our method proved viable in selective screening for differential diagnosis of endometrial pathology and cancer detection.

[Quality of life of patients with breast cancer receiving hormonal therapy, depending on age and marital status].

Our study involved 247 patients with histologically verified breast tumors, aged 48-89, who had received hormones - tamoxifen as first-line therapy, exemestan (second-line) for 12 months. FACT-B and FACT-G questionnaires were used to assess quality of life. Worse results were reported in tamoxifen-treated patients older than 60 years. Indices of emotional and social security in the two groups: 60-70 year-olds (10.8+/-0.96% and 14.3+/-1.27% vis-à-vis 14.8+/-1.31% and 15.6+/-1.42%, respectively) and over 70 year-olds (15.2+/-1.46% and 15.8+/-1.48%, respectively). Our evidence suggested that a large-seale complex of effective psychological rehabilitation be given, particularly, to those under 60, married andlor with minors, right from the very beginning of treatment.

[Comparison of efficacy of combined use of liquid cytology and immunohistochemical assay of p16ink4 and standard procedure and high risk evaluation by polymerase chain reaction of human papillomavirus infection in diagnosing cervical dysplasia and carcinoma].

Efficacy of liquid cytology, on the one hand, and those of standard one, appraisal of high risk of cancer by polymerase chain reaction (PCR) of human papillomavirus infection and immunohistochemical assay of p16ink4 high risk in cervical carcinoma diagnosis, on the other, was evaluated PCR of high risk of cancer (dysplasia-free) was detected in 73% (n = 73), CIN I-II--78%, CIN II-III--89%, CIN III and carcinoma--100%. p16ink4 was not detected in dysplasia-free cases and it was--(16%) in CIN I-II, (89%) CIN II-III, (90%) CIN III and (100%)--in carcinoma. Hence, unlike p16ink4 expression (p < or = 0.001), a correlation between the increase in the number of those infected with papillomavirus was not significantly higher than that of dysplasia grade (p < or = 0.05). It is suggested that combined use of liquid cytology and immunohistochemical assay of p16ink4 is more effective.

[The possibility and prognostic value of secondary lymphatic cancer spread in intrapulmonic metastases of solid tumors].

In the period from 1996 to 2007 operations were fulfilled in 120 patients with isolated pulmonary metastases of solid tumors (68 men and 52 women aged from 22 through 77 years): 46 patients with metastases of colorectal cancer, 28 - with cancer of the kidney, 23 - with non-small cell carcinoma of lung, 7 - with breast cancer, 9 - with endometrium cancer, 7 - with melanoma. Altogether there were 128 operations. The operations have revealed lesion of intrathoracic lymph nodes in 29 patients (24%). In most cases (21 patients) they were lesions of lymph nodes of the lung root and intrapulmonary lymph nodes. In 93% of cases (27 patients) localization of the lesion coincided with anatomical pathways of lymph outflow from the affected part of the lung. The survival rate median of the operated patients who had alterations in the lymph nodes was 21 months, in cases with intact lymphatic system it was 37 months. A conclusion is made of possible secondary lymphatic cancer spread from intrapulmonary metastases of solid tumors and its negative influence on results of treatment that allows recommendation of revision of the lymphatic system of the lungs and mediastinum in all cases of surgical treatment of intrapulmonary metastases, and in a number of cases recommendation of anatomical resections of the lung tissue as operation of choice.